The invention relates to methods of identifying improved vaccine nebulisers and nebulisers comprising those improvements. Vaccines include, but are not limited to measles vaccines. The method allows the rapid identification of nebulisers suitable for testing as vaccine nebulisers via easily testable criteria. It also allows the nebulisers to be optimized for use in the field.
In 2000, WHO (World Health Organization) estimated that there are still 30 million cases of measles each year causing 777,000 deaths. Measles vaccine is highly effective but does not achieve its full potential, in part due to logistical constraints of administering a vaccine by injection to large populations in resource-poor settings. A live attenuated measles vaccine was first developed in the 1960s and has been used ever since, with a reasonable degree of success. Its use has led to an estimated global reduction in measles incidence by about 72% and in measles mortality by 85% (Cutts F. T. et al. Alternative Routes of Immunization: A Review. Biologicals (1997), Vol. 25, pages 323-328). However the remaining burden of disease is due to the under-utilisation of the current measles vaccine. Failure to deliver at least one dose of measles vaccine to all infants remains one of the leading causes for the high measles morbidity and mortality that exists today. In addition, a number of safety concerns regarding the use and adequate disposal of syringes and sharps have been documented in a number of countries in recent years.
Delivering the current measles vaccine via the respiratory route might overcome several of the problems. It could be administered by trained lay people and avoids both the spread of blood-borne pathogens and costly disposal of needles and syringes. It would be useful for mass vaccination but also for routine immunization. By potentially reducing the need to use sharps and decreasing recurrent costs, aerosol administration of measles vaccine could make safe measles vaccination more affordable in resource-poor situations.
Respiratory administration of live measles vaccine closely mimics the natural route of measles infection. It is already established that current measles vaccines are more effective or equivalent in inducing antibody production when delivered by nebulisation compared to when delivered parenterally. Maternal antibody interference might be avoided or mucosal immunity might be enhanced. No increase in adverse side effects of respiratory administration has been noted compared to current injection practice.
Clinical studies have been carried out with aerosolized measles vaccines starting in 1983. Almost all of these studies have used the “classic Mexican” device and other variations on the Mexican model.
The classic Mexican prototype device comprised the following components:
    1. A car battery or mains electricity powered compressor attached to:    2. A commercially available nebuliser (C4107 from IPI Medical Products, Chicago, USA) attached to a vessel containing measles vaccine. This sat in a vessel of crushed ice.    3. The nebuliser was attached to a flexible Teflon™ tube via a T-piece.    4. The Teflon™ tube comprised a Teflon™ cone with a disposable paper cone as an inset.
No significant increase in adverse events in either recipients or vaccinators have been noted although follow up was sometimes short or not described. Aerosol administration directly compared with subcutaneous injection resulted in fewer reports of adverse events of symptoms of measles disease in the 2 weeks following the vaccination (Sepúlveda-Amor J., et al. A Randomised Trial Demonstrating Successful Boosting Responses Following Simultaneous Aerosols of Measles and Rubella Vaccines in School Age Children. Vaccine (2002), Vol. 20, pages 2790-2795; Dilraj A., et al. Response to different Measles Vaccine Strains Given by Aerosol and Subcutaneous Routes to Schoolchildren: a Randomised Trial. Lancet (2000a), Vol. 355, pages 798-803). Adverse events assessed included cough, conjunctivitis, rhinitis and sore throat as well as fever, headache and diarrhoea. Rubella vaccine was also studied.
In summary, in children over 9 months old, aerosol administration of EZ strain is the most effective and most extensively tested of all the non-invasive routes of administration. There is some evidence that aerosol administration can evade maternal antibody but it is not clear from the few studies comparing subcutaneous and aerosol EZ in infants less than 9 months old which route is superior (Cutts F. T., et al. (1997) Supra). In this age group there have been some practical difficulties in administration and stable seroconversion was often not established until 3-6 months after vaccination.
Two clinical studies using Serum Institute of India Ltd. (SILL) E-Z measles-containing vaccines have been carried out in Mexico.
One, using SIIL's combine measles, mumps, rubella vaccine (MMR) was done in 2000 in 100 adults. Aerosol vaccination using the classical Mexican device (50 adults) was compared to the same vaccine given by the currently approved subcutaneous route (50 adults). All subjects were healthy and were tested before the study to show they were measles immune. Differences seen in safety parameters (post auricular swelling and otitis) were likely related to the mumps component. There was a slightly higher rate of lethargy in the aerosol group—but this could be related to any of the three MMR antigens. All other adverse events observed (fever, cough, rhinitis, influenza) were less in the aerosol group than in the s.c. group. A boosting effect was seen in both groups.
A study was carried out in 2002-2003 in Queretaro State, Mexico, using SIIL measles vaccine in infants of approximately 9 months of age with no history of measles disease or measles vaccination. Follow-up and data evaluation have been submitted for publication. The vaccinations were administered to 99 infants, 53 who received measles vaccine by subcutaneous injection and 46 who received measles aerosol vaccination using the classical Mexican device. Results showed that the aerosol group had lower overall seroconversion and lower cell mediated immunity than the subcutaneous group, but the aerosol dose was determined to be more than 10 fold lower in the aerosol group (2.81 logs vs 4.28 logs). The investigators considered this to be the reason for the lower response by aerosol. However, among those children that developed a measles-specific response, the measles antibody and T cell responses were comparable. There were no serious adverse events. Fever was slightly higher in the aerosol group.
There are a number of problems associated with the “classic Mexican” device, not least is that it is not suitable for mass vaccinations in remote parts of the world. The device was difficult to use, bulky, required large batteries or mains powered sources and did not produce consistent results. Dosages were calculated by timing the inhalation period. Hence, the amount of PFU (plaque forming units) could vary from 2800 to 4000 PFU per child (Fernandez-de-Castro J., et al. Salud Pulica Mex. (1997), Vol. 39, pages 53-60). Furthermore, components such as the compressor were found not to be suitable for human use. The compressor needed shutting off between doses and was heavy and not easily portable. Moreover, the compressor used high pressures.
Other problems observed with the device included that some measles vaccines lose their potency due to the raised compressor pressures, even with crushed ice. Furthermore, concerns have been raised about reflux of respiratory pathogens into the device and from the patient interface and subsequent transmittal to other patients. The device does not allow the individual components to be easily washed and sterilized.
Alternative methods of administering measles vaccine have been tried using a foot pump attached to a nebuliser (Khanum S., et al., Lancet, (Jan. 17, 1987), pages 150-153). Two strains of vaccine were tried, the Edmonston-Zagreb and the Schwarz vaccine. The simple nebuliser used failed to give as food results as the Mexican studies or studies in the Gambia.
Handheld single dose metered devices for administering individual doses are known.
U.S. Pat. No. 5,215,079 discloses a metered dose inhaler for immunising a patient with a vaccine. The inhaler comprises a canister filled with a drug composition or a vaccine and propellant, a metering valve for emitting the vaccine or drug and an interlock that prevents more than one dose being administered. The device is usually only filled with one dose of vaccine or drug and is disposed of after use. This precludes its use in situations where large numbers of vaccinations are required because of difficulties in transporting large numbers of such single dose inhalers to often remote locations.
Such a device uses the lungs or nasal surfaces to absorb the active drug or vaccine.
US 2003/064032A discloses an alternative aerosol device for delivering drugs, such as insulin, comprising using an atomizer. This produces aerosols with an average droplet size of typically 5 μm. This device is aimed at personal insulin inhalation.
U.S. Pat. No. 5,497,944 discloses metered dose inhalers, liquid medicaments in the form of an atomiser for dispersing medicaments, in solution. The device is a handheld, single user device, ideally suited to individual use.
WO 02/074372 discloses aerosol delivery devices for delivering aerosols into a patient. Such devices are stated to include jet aerosolisers and pneumatic and ultrasonic devices. They are exemplified as being suitable for a wide range of different agents, including pharmaceuticals, chemotherapeutics, immune reagents and vaccines. The size of droplets presented in the patent application range from 5-10 microns.
WO2006/006963 (published 19 Jan. 2006) discloses modified aerosol delivery devices for a wide range of uses comprising removable aersolising elements having movable elements to expel agents from a chamber.
WO 02/43705 discloses aerodynamically light particles for vaccine delivery to the pulmonary system. The particles are stated to have a mean mass diameter of 5-30 micrometers. A wide range of alternative sizes for the particles is referred to in the document.
The generation of therapeutic aerosols depends on the comminution of liquids into small particles. In the case of vaccines such as measles, the antigen is usually contained within small liquid droplets or particles. The energy for this process is usually produced by compressed air passing over the liquid.
There are a wide variety of variables involved in the identification of nebuliser and compressor design and selection for vaccination, rather than drug (such as salbutamol) administration. Previous trials have used a variety of different pressures, nebulisers, compressors, etc. Compressors, for example, have varied from 30-200 psi and the actual pressure applied has not always accurately been stated. Particle size has also been shown to vary and there is a need to optimise the average size produced to ensure that the particles are efficiently delivered to the lungs of a patient.
The Applicants have now identified a number of parameters and modifications to be made to nebulisers in order to optimise nebulisers for use in the administration of vaccines such as measles vaccine, especially with respect to large scale vaccination programs. This is important as previously it has been necessary to trial nebulisers to see whether they have any potential for use in vaccine development. By identifying the parameters for suitable nebulisers which can be tested within the laboratory, this considerably reduces the numbers of nebulisers which need to be tested for their ability to be used with vaccines.
Other devices for administration of measles and other vaccines have been considered by the Applicants. These include nasal sprays. However, a problem associated with nasal sprays is that upper respiratory tract infections often interfere with it. The devices produce mean particle sizes of about 70 microns. These large particles often do not pass past the vocal cords. As measles vaccine is thought to be ideally absorbed by the lower respiratory tract, the size of the particles produced by nasal sprays are thought to be a major problem.
Dry powder delivery has also been considered. However, initial results by the Applicants indicated that the dry powder is often deposited in the large bronchi and not properly taken into the lower respiratory tract. Furthermore, there may be difficulties with infants because of the relatively large doses required to administer the required amount of vaccine.
U.S. Pat. No. 6,630,169 discloses compositions and methods for the administration of particulates. Such particulates may be in the form of dry powders or combined with non-aqueous media to form stabilised dispersions. The compositions may be used in conjunction with metered dose inhalers, dry powder inhalers, atomisers or nebulisers, but also suggests topical, intramuscular, transdermal, intradermal, intraperitoneal, vaginal, rectal and occular administration routes for the particulates. Vaccines, microbes, vectors, polypeptides, proteins, carbohydrates and peptides are among the many different biologically active materials suggested in the patent. The patent is concerned with the production of specific dry powder formulations which have reduced clumping of the particles. The document speculatively suggests a wide range of particle sizes for the dry particles of between 0.5 μm and 50 μm, with preferred mean geometric dry particle sizes of less than 20 μm or even less than 1 μm. The spread sizes of particles are not provided in the document.